The Role of IL-17 Axis in Inflammatory Myositis

描述（由申请人提供）：皮肌炎（DM）是一组罕见但危及生命和器官的自身免疫性综合征的例证，统称为特发性炎症性肌炎（IIM）。糖尿病患者会出现衰弱性肌肉无力、呼吸障碍和毁容性皮疹。糖尿病的器官损伤与全身和局部的强烈炎症和免疫反应有关；然而，免疫功能障碍的关键细胞和分子研究者尚不清楚。我们最近的基因组学和蛋白质组学研究揭示了糖尿病疾病活动性与促炎细胞因子白介素-17 （IL-17）和i型干扰素（IFN）调节的趋化因子的血清水平之间的显著关联。此外，在糖尿病患者和实验性肌炎啮齿动物的肌肉活检中检测到高水平的IL-17和ifn相关趋化因子。这些观察结果使我们假设：a) IL-17和相关分子的增加将作为糖尿病疾病活动性和严重程度的敏感生物标志物；b) IL-17轴和i型ifn相关趋化因子的失调是糖尿病免疫病理的关键驱动力。我们建议使用基因组学、免疫组织化学和生化方法来验证这些假设。首先，我们将确定病变人类DM肌肉中IL-17的精确解剖和细胞位置，并确定肌炎动物模型中IL-17的需要量和充分性。其次，我们将在梅奥诊所DM患者的纵向研究中评估测量外周血中IL-17轴成分和ifn相关趋化因子的预测和诊断价值。最后，我们将探讨拮抗IL-17轴在肌炎中的治疗价值。通过注射抗IL-17抗体，我们将确定阻断IL-17功能是否可以改善或预防肌炎小鼠模型中的肌肉损伤。这些实验产生的数据将为糖尿病的免疫发病机制提供新的线索，将为糖尿病疾病活动性评估建立新的生物标志物的价值，并将量化IL-17操纵在炎症性肌炎中的治疗潜力。

DESCRIPTION (provided by applicant): Dermatomyositis (DM) exemplifies a group of uncommon but life- and organ-threatening autoimmune syndromes collectively known as idiopathic inflammatory myositis (IIM). Patients with DM suffer debilitating muscle weakness, respiratory impairment, and disfiguring skin rashes. Organ damage in DM is associated with intense inflammatory and immune reactions, both systemic and local; however, the key cellular and molecular investigators of immune dysfunction are unknown. Our recent genomic and proteomic studies reveal striking association between DM disease activity and serum levels of the pro-inflammatory cytokine interleukin-17 (IL-17) and type-I interferon (IFN) regulated chemokines. Further, high levels of IL-17 and IFN-related chemokines are detected in muscle biopsies from both DM patients and from rodents with experimental myositis. These observations lead us to hypothesize that a) increased IL-17 and related molecules will serve as sensitive biomarkers of disease activity and severity in DM and b) dysregulation of the IL-17 axis and the type-I IFN-related chemokines are a key driving force in the immunopathology of DM. We propose to test these hypotheses using genomic, immunohistochemical, and biochemical approaches. First, we will determine the precise anatomic and cellular location of IL-17 in diseased human DM muscle and determine the requirement for and sufficiency of IL-17 in a myositis animal model. Second, we will assess the predictive and diagnostic value of measuring peripheral blood components of the IL-17 axis and IFN-related chemokines in a longitudinal study of Mayo clinic DM patients. Finally, we will explore the therapeutic value of antagonizing the IL-17 axis in myositis. Using injectable anti-IL-17 antibodies, we will determine whether blocking IL-17 function can ameliorate or prevent muscle damage in a mouse model of myositis. Data arising from the proposed experiments will shed new light on the immunopathogenesis of DM, will establish the value of novel biomarkers for DM disease activity assessment, and will quantitate therapeutic potential of IL-17 manipulation in inflammatory myositis.